If you’ve heard of mitochondrial disease it will probably be because of the “three person IVF” headlines in the news over the past 12 months, about a new technique that aims to prevent these diseases. Then again, you may have not realized that had anything to do with mitochondria, whatever they are. The Wellcome Trust Centre for Mitochondrial Research at Newcastle University, which celebrates its one year anniversary today, is one of the pioneers of the new IVF technique, but is also investigating mitochondrial disease in other ways that aren’t so headline-grabbing that could make a real difference to those affected.

Mitochondria are the ‘power packs’ of cells, tiny bodies in the cells that provide the energy for the cell’s activities. In the distant evolutionary past, mitochondria lived as miniscule organisms in their own right and so have their own DNA, mitochondrial DNA (mtDNA), which they use to make the proteins they need. Then, one of our single-celled ancestors engulfed one, and they’ve been in our cells ever since. Nowadays, they are no longer self-sufficient — some of the proteins needed by mitochondria are coded in the DNA in our nucleus. So a mutation in either mitochondrial DNA or the nuclear DNA that codes for mitochondrial proteins can lead to mitochondrial disease.

Nuts and bolts: mitochondria

The symptoms can differ massively between people. Since mitochondria provide energy, any mitochondrial dysfunction has more effect in the muscles, brain and heart, since these tissues require the most energy. It can also affect hearing, pancreatic beta cells (the cells damaged in diabetes) and the eye. This can cause devastating disease. Around 1 in 200 babies in the UK are born with a mutation in mitochondrial DNA, with an estimated 1 in 5,000 developing a disease.

One of the most prominent is MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes), symptoms of which include seizures, problems with vision, and a build up of lactic acid, which causes extreme tiredness, muscle weakness, breathing difficulties and vomiting. MELAS is often caused by a simple swap of an adenine for a guanine base in mitochondrial DNA. This most common of mitochondrial DNA mutations makes 1 in 400 people MELAS carrying the mutation, even though most don’t show symptoms.

The variability of mitochondrial disease is one of its biggest challenges. A recent paper from the Wellcome Trust Centre looked into the symptoms of patients with that common MELAS mutation. Only 10 per cent of those tested had the symptoms of MELAS, 30 per cent had maternally inherited deafness and diabetes and 28 per cent had symptoms not matching any of the classic mitochondrial disorders. But though the symptoms may be variable, understanding the underlying genetics does help.

For Professor Doug Turnbull, Director of the Wellcome Trust Centre, one of the most exciting things to come out of their research is that, through genetics, they can now establish a diagnosis in many of the children affected with mitochondrial disease. Unfortunately, there is currently no cure for mitochondrial disease —treatments deal with the symptoms, not the cause. So if a patient has a heart problem, they will be given cardiac drugs, if a patient has epilepsy they will be given anti-convulsants. Turnbull, however, is optimistic that a specific mitochondrial treatment will be developed as genetic technology becomes more sophisticated. In the meantime, the Centre’s researchers are working hard to prevent mitochondrial diseases being passed on in the first place. “Even though we can’t treat the disease, we can actually give them a genetic diagnosis and that allows them to have reproductive choice,” says Turnbull, allowing people at risk of passing on mitochondrial disease the freedom to decide whether to have children or not.

Mitochondrial DNA is passed down through the mother, since it’s the mitochondria in her egg cell that are passed on to the new embryo. The news-grabbing IVF technique is likely to be the most effective preventative method. But other techniques exist that help prevent mitochondrial disease. Pre-implantation genetic diagnosis (PGD), for example, is a common screening process testing a single cell from each embryo created in an IVF procedure. This can be used to find which have the lowest amount of mutated mitochondrial DNA so that the healthiest embryo can be implanted into the womb. Although not suitable for all couples, PGD is reducing the risk of passing on mitochondrial diseases for many parents.

Patients with mitochondrial disease from all over the UK come to Newcastle for the Centre’s expertise, and the link between research and patient care is paramount. For Turnbull, the patients inspire new questions about the similarities and differences between mitochondrial diseases, the answers to which will hopefully lead to new treatments. And they pose further questions too. Turnbull’s background is in neurology and one of his interests is investigating why so many patients with mitochondrial disease get generalised epilepsy, which alters electrical activity throughout the brain (other forms of epilepsy only affect small areas of the brain). “If you’ve got a brain that is already lacking in energy [because of faulty mitochondria] and is already vulnerable, these seizures are going to be more harmful, ” says Turnbull. His team is investigating whether this is down to a specific cell type found throughout the brain being affected, which, if so, could lead to better, more specific treatments for mitochondrial-based epilepsy.

The Centre is also interested in the effect of mitochondrial DNA mutations on more common diseases. Their study of mitochondrial disease could therefore lead to potential treatments for age-related diseases such as Parkinson’s and cancer. For example, Turnbull’s team has found that some mitochondrial disease patients had fewer neurons producing dopamine —a brain signaling chemical — in their brain. These are known to degenerate in Parkinson’s disease, so a mitochondrial-based treatment to stop it could potentially be used to treat Parkinson’s disease.

Despite the recent publicity around mitochondrial transfer, most people don’t know or understand why this was being done. At the height of the three parent headlines, the Human Fertilisation and Embryology Authority ran a public consultation last year about the new IVF technique. But when they approached random members of the public, none remembered seeing any of the publicity. “Nobody had drawn the conclusion that [three person IVF] was mitochondria,” says Turnbull. And with the misunderstanding and ensuing controversy, the process of getting ethical approval to develop the technique and make it available for patients has not been easy, “It’s been a huge amount of time… a huge learning curve,” says Turnbull. “I’ve been hugely helped by all sorts of people and we wouldn’t be where we are if we didn’t have the Wellcome Trust.”

The hard work paid off; on 27th June, the UK government approved the new mitochondrial transfer technique and will issue draft regulations later this year for further public consultation. We’re on our way to replacing those broken batteries.

Related

My husband was diagnosed in February 2013 with MELAS. He has now had his second episode in November 2013. The impact on us as a family has been huge. And the financial implications have been even bigger. No one has given us any voluntary information as the benefits he is entitled to, as he is not able to work at all. It has been a struggle as I have no experience of benefits at all, so am having to muddle my way through with no help. Have also had to deal with his psychological impairments with minimal help. Can you not develop a tool which addresses the practical benefits needed and the ongoing help which will be needed in the future due to deterioration? It has been so difficult so far without any help… Help!!

Dear Wendy – thanks for sharing your experience here. I understand that the difficulty of finding out what financial assistance you may be entitled to and how to get it creates additional stress and uncertainty on top of coming to terms with your husband’s diagnosis this year and what that means medically. I’ve put you in touch with an NHS welfare rights advisor, who I hope will be able to help you. Best wishes, Michael

The Wellcome Trust Centre for Mitochondrial Research has lots of information on its website: http://www.newcastle-mitochondria.com/
If you are affected by mitochondrial diseases and have specific questions, you can contact their experts and advisors through that site as well.

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